Clinical Translational Aspects in Bone Regeneration: From Bench to Bone

Bone is a dynamic and resilient tissue that constantly remodels itself to adapt to the body’s needs. Unlike many tissues, such as skin, which heal by forming scar tissue, bone has the unique ability to regenerate and repair itself without scarring. However, in cases of severe bone injuries, natural healing processes may be insufficient, necessitating surgical intervention. Critical-sized or non-union bone defects refer to injuries that cannot heal on their own and require clinical treatment. The current gold standard for managing such defects is autologous bone grafting, which involves harvesting bone from one part of the patient’s body and transplanting it to the injury site. While effective, this approach has significant limitations, such as a limited supply of donor bone, prolonged surgical times, and potential complications at the donor site, including pain and infection. These issues underscore the pressing need for improved treatment methods, as bone defects pose substantial clinical and socioeconomic challenges. They often result in extended recovery times, disability, and increased healthcare costs. Epidemiological data highlight the growing burden of bone defect treatment, emphasizing the importance of innovative solutions.

Bone tissue engineering (BTE) offers a promising alternative to traditional methods by aiming to regenerate or replace damaged bone. One advanced approach within BTE is endochondral bone regeneration (EBR), which mimics the body’s natural process of bone development. EBR utilizes a cartilage intermediate that gradually transforms into bone, harnessing the body’s regenerative pathways. This process involves implanting an engineered cartilaginous structure containing specialized chondrocytes and a hypertrophic matrix, which the body remodels into bone. By replicating the natural progression from cartilage to bone, EBR addresses limitations of traditional grafting, such as the scarcity of donor material and complications associated with harvesting bone. Preclinical studies have shown that EBR has great potential for improving bone healing and regeneration, making it a promising strategy in BTE.

In BTE applications, stem cells can be differentiated in the lab to create cartilaginous constructs that are implanted into the patient. However, challenges remain in obtaining sufficient stem cells and ensuring their reliable differentiation into cartilage. Using allogeneic (donor) stem cells could address this issue, but it raises concerns about immune rejection. Another innovative solution is the use of devitalized constructs, in which the cells are removed, leaving behind a matrix rich in growth factors that promote bone regeneration. This thesis explores the effects of devitalized allogeneic stem cell-derived cartilage matrices on immune responses and bone healing. Studies in goats, which have physiological similarities to humans, demonstrate the feasibility of this approach in a large animal model.

A significant challenge in creating engineered tissues for clinical use is ensuring adequate vascularization to support tissue viability. This thesis investigates various vascularization strategies to address this bottleneck. One study employs a 3D co-culture model to preserve small blood vessel networks in environments conducive to bone formation. Another explores biofabrication techniques to advance vascularization and critically analyzes current limitations in BTE. Finally, the use of an arteriovenous (AV) loop is examined as a method to create blood vessels within large engineered constructs.

The goal of this research is to advance the clinical application of EBR for large-scale bone defect treatment. By bridging the gap between laboratory research and clinical practice, these findings provide a foundation for future innovations in bone tissue engineering.